Many scientists have sought to treat cancer by activating the immune system against the tumor. However, despite occasional successes, durable responses to immune therapy have been rare and limited to just a few tumor types. Current understanding of cancer immunotherapy among those skilled in the art has been summarized in recent review articles, including for example Chen and Mellman, Immunity 2013 39(1): 1-10. The cycle for induction of therapeutic immune responses against tumors may be broken down into seven distinct steps (FIG. 1):
1. Release of cancer cell antigens;
2. Presentation of cancer cell antigens by antigen-presenting cells (APC, usually in draining lymph nodes);
3. T-cell priming and activation;
4. Trafficking of CD8+ T cells to tumors;
5. Infiltration of CD8+ T cells into tumors;
6. Recognition of cancer cells by the infiltrating CD8+ T cells; and
7. Killing of cancer cells.
The art teaches that there are multiple negative and positive mediators of each step of the anti-tumor response. Recent research interest has focused on understanding and addressing the role that negative mediators play in inhibiting the anti-tumor immune response. For example, interleukin-10 (IL-10) is a factor that can have complicated effects, locally immune suppressive in the tumor, but systemically can actually have anti-tumor activity (reviewed in Vicari and Trinchieri, Immunol. Rev., 2004). Although Toll-like receptor (TLR) agonists such as TLR9-activating CpG oligonucleotides (CpG ODN) have immune stimulatory effects that can promote anti-tumor responses, they are also known in the art to induce immune suppressive factors such as IL-10 (reviewed in Lu, Frontiers Immunol, 2014). The art does not teach designs of TLR9 agonists that have improved anti-tumor effects as a result of inducing lower amounts of IL-10 production. Nevertheless, this increasing recent understanding of the cycle of tumor immunity has heightened awareness that it may be possible to increase the clinical efficacy of cancer immunotherapy by using combinations of agents that act at different points in this cycle for induction of therapeutic immune responses against tumors, but the art does not provide a deep enough understanding of the immunobiology of cancer to predict which of the many different possible combinations will be preferred.
Another possible way to consider the development of the anti-cancer T-cell response is the 3-signal model for the induction of a T-cell response, summarized by Kim and Cantor, Cancer Immunol Res 2014 2:929-936) and presented in FIG. 2. In this model signal 1 to the T cell come from the presentation of antigen by an APC on the appropriate MHC to the T cell receptor. Signal 2 is the requirement for a costimulatory signal through the interaction of CD28 on the T cell by B7-1 or B7-2 on the APC (this signal is antagonized by CTLA-4 present on Treg: the efficacy of anti-CTLA-4 antibodies in cancer immunotherapy results from their inhibition of this “off” signal). Finally, signal 3 is the modulation of T cell function resulting from signals via inflammatory cytokine receptors and PD-1. In particular for the induction of optimal CD8+ T cell responses, which are known to be critical for successful cancer immunotherapy, type I IFN signaling is a very positive signal, but when chronic or prolonged also can paradoxically lead to T cell exhaustion and unresponsiveness, which is mediated through upregulation of PD-1 expression. Blocking of PD-1 by antibodies to it, or against its major ligand regulating anti-tumor immunity, PD-L1, therefore restores the ability of the T cell to proliferate and produce cytokines in the tumor microenvironment.
Recently there have been several early clinical successes with the use of “checkpoint inhibitor” (CPI) compounds, such as antibodies, which block the negative immune effects of the checkpoint molecules such as CTLA-4, PD-1, and its ligand, PD-L1. Systemic administration of anti-CTLA-4 antibodies has led to durable responses in ˜10% of patients with melanoma, and some encouraging early results in other tumor types, but at the cost of a high rate of adverse effects, including death in some patients. Anti-PD-1/PD-L1 human clinical trials also have been reporting encouraging results, apparently with a lower rate of severe toxicity. However, analyses of the responding patients have revealed that across multiple different types of cancer, responses to anti-PD-L1 therapy are relatively restricted to patients with tumor-infiltrating lymphocytes (TIL) and a Th1 pattern of gene expression in the tumor (Powles et al., Nature 2014 515:558; Herbst et al., Nature 2014 515:563; Tumeh et al., Nature 2014 515:568). That is, responses can be seen in some patients with preexisting immunity to the tumor, but are quite unlikely to occur in patients without this. Aside from melanoma, in which pre-existing anti-tumor immunity is relatively common, TIL are relatively uncommon in most other tumor types, indicating that CPI may be of limited benefit in most types of cancer. Thus, there is a need to improve the efficacy of CPI for cancer therapy.